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Page 6 of 14 Orekhov et al. Vessel Plus 2019;3:3 I http://dx.doi.org/10.20517/2574-1209.2018.80

CIC potentiate the atherogenicity of desialylated LDL causing higher cholesterol accumulation in cultured
cells [5,9,10] . The addition of the complement component and fibronectin to the LDL autoantibody complex
C1q resulted in a more pronounced accumulation of intracellular cholesterol. Thus, the formation of CIC
is the actual mechanism for enhancing the atherogenic capacity of desialylated LDL. In addition to the
accumulation of lipids, the CIC induces the secretion of pro-inflammatory cytokines and apoptosis of
[12]
macrophages which can also be considered as pro-atherogenic effect. Recent studies of LDL containing
CIC focus mainly on implementation into clinical practice for diagnostics (see below).

FOAM CELLS AND ATHEROGENESIS
Intracellular lipid accumulation leading to foam cell formation is the most noticeable and earliest
manifestation of atherosclerosis. However, other manifestations are also generally recognized: (1) an increase
in the proliferative activity of the leader leading to hypercellularity; (2) the enhancement of synthesis of the
extracellular matrix, leading to the growth of connective tissue; and (3) the loss of intercellular contacts
leading to rupture of the cellular network in the intima and detachment of intimal cells [5,14] . Examined was
the effect of circulating desialylated LDL on proliferative activity and synthesis of total protein, collagen and
glycosaminoglycans by SMA+ cells cultured from uninvolved human aortic intima.

3
A 24 h incubation of SMA+ cells with native LDL had no effect on proliferative activity detected as [ H]
[5]
thymidine incorporation into cultured cells . By contrast, addition of desialylated LDL subfraction leads to
a 1.5- to 2-fold increase of proliferative activity.

14
The rate of synthesis of proteins secreted by cultured cells was evaluated by incorporation of [ C]leucine in
the acid-insoluble fraction of culture medium. Native LDL had no effect on the synthesis of secreted proteins.
[5]
Desialylated LDL stimulated protein syntheses by 1.5- to 2-fold . Moreover, desialylated LDL induced a
14
2-fold increase of collagen production, as estimated by incorporation of [ C]proline in the collagenase-
[5]
released fraction of culture medium . It was also demonstrated that desialylated LDL, but not native LDL,
14
stimulates the incorporation of [ C]glucosamine in the total glycosaminoglycan fraction of human SMA+
[5]
cells . So, in contrast to native LDL, desialylated LDL enhanced synthesis of connective tissue matrix
components.
It was shown that: (1) desialylated LDL-induced lipid accumulation is sufficient to enhance proliferative
activity and stimulates the incorporation of precursors of the extracellular matrix components; (2) insoluble
complexes of native LDL with naturally occurring (collagen, elastin, fibronectin) and artificial (latex
particles, dextran sulfate) compounds induce intracellular lipid accumulation and stimulate proliferative and
synthetic activities; and (3) the increase in proliferative and synthetic activities correlates with the amount
[5]
of accumulated intracellular cholesterol . In addition, after incubation of SMA+ cells with desialylated LDL,
[14]
intercellular communication through gap junctions was dropped considerably . These findings indicate
that intracellular lipid accumulation might be a reason for the disintegration of cellular network observes in
atherosclerotic lesions.

Thus, foam cell formation induced by desialylated LDL causes enhanced proliferative activity, the synthesis
of the connective tissue matrix components and also breaks intercellular communication. Therefore,
desialylated LDL can induce all known atherosclerotic manifestations at the cellular level.

The interaction of atherogenic modified LDL with macrophages causes a pro-inflammatory response
which, if unfavorable, develops into a local chronic inflammation characteristic of atherosclerotic lesions.
In primary human monocyte-derived macrophages, modified LDL-induced cholesterol accumulation is
[15]
accompanied by upregulation of genes encoding pro-inflammatory molecules . It is unclear whether foam
cell formation induces a pro-inflammatory response or pro-inflammatory response promotes cholesterol
accumulation. It was demonstrated that local cellular responses to oxidized LDL may stimulate pro-